The present invention relates to the use of certain 17-ketosteroids in the prophylaxis and therapy of retroviral infections or a complication or consequence thereof. In particular, the invention relates to the use of said 17-ketosteroids in the prophylaxis and therapy of retroviral infections leading to a deficiency of the immune system resulting in the development of opportunistic infections and certain cancers. More especially, the invention relates to the use of the 17-ketosteroids in the prophylaxis and therapy of retroviral infections thought to be responsible for the Acquired Immune Deficiency Syndrome (AIDS) and the related disease AIDS related complex (ARC). AIDS and ARC are believed to result from infection by the Human Immunodeficiency Virus (HIV) and antibodies to which are found in the serum of almost all persons diagnosed as suffering from AIDS or ARC. Lymphadenopathy-associated virus (LAV) and human T-lymphotrophic virus type III (HTLV-III), as well as related retroviruses have been isolated from a large number of AIDS patients. All of these viruses share important characteristics. HTLV-III and LAV are now believed to be strains of the same virus, which has been given the name Human Immunodeficiency Virus (HIV).
AIDS is a disease characterised by loss of cell-mediated immunity and the development of frequent and eventually fatal opportunistic infections. The diagnosis of AIDS is a clinical one, defined as "the occurrence of an illness predictive of a defect in cell-mediated immunity occuring in an individual with no known cause for diminished resistance to that disease" (Lane, H. C. & Fauci, A. S. Ann. Rev. Immunol. 1985, 3, 477-500).
The use of the term HIV embraces the retrovirus HIV-1 or HIV-2 (Human Immunodeficiency Virus Type 1 and Human Immunodeficiency Virus Type 2), which was discovered in 1983. HIV attacks and reduces the numbers of a subset of white blood cells known as T lymphocytes. Expressed on the cell surfaces of these T lymphocytes is a molecule known as CD4, (such cells are also known as T4 cells). Such lymphocytes, most of which are included in what is functionally defined as the helper/inducer subset, constitute the major proportion of mature T cells. Another major subset of T cells express the CD8 molecule on their cell surfaces (such cells are also known as T8 cells). Most of these are classified as suppressor/cytotoxic cells. Normally the T4/T8 ratio is 1.5 to 2.0. In AIDS patients, however, this ratio is inverted due to a decrease in the absolute numbers of T4 cells, with normal numbers of T8 cells usually being preserved.
T4 cells specifically recognise and proliferate in response to antigens that they encounter in the body, at the same time releasing a variety of proteins known as lymphokines that regulate other immune system cells. Upon signaling by T4 cells, B lymphocyte cells recognise antigens and secrete specific antibodies to neutralise or eliminate antigenic bacteria and viruses as they travel through body fluids between cells. Similarly, following signaling from T4 cells, cytotoxic T cells ("T8") become activated to kill cells infected with intracellular pathogens. Furthermore, T4 cells modulate the activities of immune system cells known as natural killer cells and macrophages, which are involved in response to infection and perhaps to incipient malignancies.
A critical and early event in HIV infection involves the virus' attachment, via its envelope glycoprotein, to a receptor on the surface of a susceptible T4 cell, the CD4 molecule. The CD4 molecule at the T4 cell surface appears to distinguish potential target cells from HIV and to act as the receptor molecule that binds the virus and allows infection and subsequent viral replication as well as the cytopathic consequences of viral infection.
The immunodeficiency of AIDS clearly demonstrates the importance of T4 lymphocytes. Because of the loss of these cells, the remaining T lymphocytes from AIDS patients have diminished or absent responses to antigens and show subnormal production of essential immuno-regulatory factors. Due to their decreased numbers and functional capacity, T4 cells are unable to fulfil their necessary role in providing direction for the maturation of B cells and cytotoxic T cells. The ability of AIDS patients to mount antibody reactions to new antigens is severely compromised, though paradoxically high levels of antibodies to previously encountered antigens, including HIV, are often present in patient' sera (Institute of Medicine, National Academy of Science, Confronting AIDS, Washington, D.C. National Academy Press 1986, pages 37-44 and 177-199).
At present AIDS and ARC are predominantly found in certain high risk groups such as homosexuals, intravenous drug abusers and those who have received multiple transfusions or products such as Factor VIII derived from blood. Blood donors are now routinely screened for antibodies to HIV and, therefore, future spread of HIV through blood transfusions and blood-derived products should not, hopefully, lead to transmission of AIDS. AIDS is also increasingly found in the heterosexual population.
There is increasing evidence that macrophage/monocyte infection is a vital factor in the persistence and progession of HIV infection, in initiating the brain damage that occurs in AIDS and in triggering the collapse of the immune system as evidenced by eventual profound depletion of T4 lymphocytes. Crowe et al. have demonstrated using anti-HIV p24 antibody that monocyte/macrophages can be infected with HIV. They have demonstrated that up to 70% of cells from individual donors could be infected (AIDS Research and Human Retroviruses, Vol. 3, No. 2, 1987, page 135). Nicholson et al. have proposed an HTLV-III/LAV-induced effect in monocyte function rather than (or in addition to) an intrinsic defect in surviving T cells to account for observed abnormalities in T cell assays that are monocyte-dependent such as pokeweed mitogen-induced Ig synthesis and proliferative responses to soluble antigens. These T cell assays have previously been reported as abnormal even when assayed as T cell subsets (The Journal of Immunology, Vol. 137, No. 1, 1986, page 323).
Since it is well established that the first event that occurs when a foreign material (for example, a virus) enters the body is its uptake by mononuclear phagocytes, it is conceivable that these cells represent a primary target for HIV. Gartner et al. have shown that virus production by HTLV-III/LAV infected macrophages was high and long-lived, indicating that these cells may play a role in virus dissemination and persistence. They have demonstrated HTLV-III/LAV replication in macrophages was fully productive in the situations they evaluated (Science Vol. 233, 1986, page 215).
Salahuddin et al. observed that in vitro pulmonary macrophages can be infected with HTLV-III and appear to be less susceptible to the phytopathic effects of this retrovirus which suggests that tissue macrophages should be considered as potential reservoirs of HTLV-III in vivo (Blood, Vol. 68, No. 1, 1986, page 281).
Ho D.D. et al. observed normal blood-derived monocytes/macrophages were found to be susceptible to infection in vitro by human T Lymphotropic virus III (HTLV-III), the etiologic agent of the Acquired Immune Deficiency Syndrome. In addition, HTLV-III was recovered from monocytes/macrophages of patients infected with this virus. It was postulated therefore that HTLV-III-infected monocyte/macrophages may serve as a vehicle for the dissemination of virus to target organs and as a reservoir for viral persistence, as has been shown for other lentiviruses, including visna virus and caprine arthritis encephalitis virus (J. Clin. Invest., Vol. 77, 1986, page 1712).
While an antiviral agent which could kill all infecting HIV or completely inhibit its replication (and at the same time have an acceptable toxicity profile) is clearly desirable, the situation is that no such agent is at present available.
With the emerging understanding of the role that macrophages may be playing in the pathogenesis of AIDS, it is clear that an effective antiviral strategy will require an approach that can treat infected macrophages and inhibit infection of these cells. Currently the only F.D.A. approved antiviral agents for treatment of AIDS are azido thymidine (AZT) and pentamidine isethionate (PENTAM 300). As demonstrated hereinafter AZT is completely ineffective at inhibiting macrophage infection or modulating HIV production from infected macrophages. Administration of AZT over long periods of time has been found to give rise to undesirable side effects such as anaemia, necessitating blood transfusion, leucopenia and neutropenia.
The great majority of antiviral compounds are nucleosides, including, for example, AZT.
Many of the 17-ketosteroids function as hormones and include sex hormones or precursors thereof and hormones which control metabolism. Dehydroepiandrosterone (DHEA) is one such 17-ketosteroid which is a precursor of both androgens and estrogens and additionally has important metabolic effects. These effects ensue from its inhibitory effect on enzymes such as glucose-6-phosphate dehydrogenase and NADH oxidase. Additionally, DHEA has an inhibitory effect on mitotic activity and on the permeability of membranes (Jiri Sonka, Acta Universitatis Carolinae Medica Monographia LXXI 1976). The effect of DHEA on enzymes such as glucose-6-phosphate dehydrogenase and NADH oxidase leads above all to inhibition of the pentose cycle and of the cytochrome system, both of which restrict the supply of building materials and energy, necessary for biosynthetic processes, in particular for growth and regeneration of tissue. One of the main conditions of growth is an adequate supply of energy (ATP) and building materials for nucleic acid synthesis. DHEA controls both of these processes as an inhibitor of NADH oxidase and glucose-6-phosphate dehydrogenase. DHEA has been found to suppress some of the metabolic disorders and liver cirrhosis, and reduces pain in ischemic heart disease, especially in angina pectoris, by restricting tissue respiration. HEA has been used in the treatment of menopause, emotional instability, depression and stress.
Individuals who are genetically deficient in glucose-6-phosphate dehydrogenase are relatively resistant to Falciparum Malaria and have much smaller numbers of protozoa in their erythrocytes than normal individuals (Motulski, A. G. 1975, in "The Role of Natural Selection in Human Evolution", Ed. Salzano, S. Amsterdam, New Holland, P. 271 and Luzzato, L. et al., Science, 164, 839, 1969).
DHEA and related compounds are capable of reducing the colony forming ability of human peripheral blood mononuclear (PBM) cells infected with Epstein-Barr virus (a herpes virus) at concentrations of 10-100 .mu.M (Carcinogenesis, Vol. 2, pp 883-886, 1981).
DHEA also inhibits complement activation and is therefore of value in the prophylaxis of Hereditary Angioneurotic Oedema (Hidvegi et al., Complement 1; 201, 1984). DHEA also prevents autoantibody formation in the murine model of Systemic Lupis Erythematosus (SLE) and many of the features of full-blown AIDS are considered to be similar to those of SLE (Lucas et al., J. Clin. Invest., 75: 2091, 1985).